| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T465 |
0-79 |
Sentence |
denotes |
HCQ explains its antitumor activity thanks to its ability to inhibit autophagy. |
| T466 |
80-144 |
Sentence |
denotes |
HCQ is, indeed, an FDA-approved drug inhibiting autophagy [135]. |
| T467 |
145-222 |
Sentence |
denotes |
Several types of tumors develop chemoresistance by enhancing autophagic flux. |
| T468 |
223-405 |
Sentence |
denotes |
Autophagy consists in the sequestration of materials in autophagic vesicles to be eliminated through lysosomal fusion and allows cells to overcome metabolic and therapeutic stresses. |
| T469 |
406-508 |
Sentence |
denotes |
By recycling intracellular components, cells may maintain an energy balance and increase their growth. |
| T470 |
509-575 |
Sentence |
denotes |
If it occurs in cancer cells, resistance mechanisms may establish. |
| T471 |
576-719 |
Sentence |
denotes |
One of the mechanisms responsible for drug resistance is related to increased drug efflux by ATP-binding cassette (ABC) transporters [136,137]. |
| T472 |
720-956 |
Sentence |
denotes |
It has been observed that HCQ is significantly reduced the increase in P-gp (ABCB1) expression and, in combination with several anticancer drugs, induced higher cytotoxicity in refractory cancers by inhibiting autophagic activity [138]. |
| T473 |
957-1073 |
Sentence |
denotes |
However, the role of autophagy in cancer is controversial and depends on genotype and tumor stage development [139]. |
| T474 |
1074-1271 |
Sentence |
denotes |
Many clinical trials examined the synergistic effects of the addition of HCQ to conventional chemotherapic drugs, finding that the role of autophagy is complex and is influenced by several factors. |
| T475 |
1272-1389 |
Sentence |
denotes |
Depending on genetic concomitant alterations, autophagy may possess both pro-tumorigenic and tumor-suppressive roles. |
| T476 |
1390-1550 |
Sentence |
denotes |
It has been confirmed in murine models of pancreatic ductal adenocarcinoma, a type of cancer with a high mortality rate, due to its refractoriness to therapies. |
| T477 |
1551-1720 |
Sentence |
denotes |
Mice presenting activated oncogenic KRAS and normal expression of p53 oncosuppressor experienced a critical regression of tumor developing under HCQ (60 mg/kg/day i.p.). |
| T478 |
1721-1941 |
Sentence |
denotes |
By contrast, in those with a deficiency of p53, the inhibition of autophagy by HCQ increased the tumor progression, demonstrating that autophagy’s role in tumorigenesis is strictly related to the expression of p53 [140]. |
| T479 |
1942-2082 |
Sentence |
denotes |
The expression of p53 is often altered in cancer, so as to be found mutated or absent in the 75% of pancreatic ductal adenocarcinomas [141]. |
| T480 |
2083-2179 |
Sentence |
denotes |
This issue highlights the necessity to carefully evaluate the use of HCQ in certain tumor types. |
| T481 |
2180-2405 |
Sentence |
denotes |
Different outcomes have been previously described, it has been found that inhibition of autophagy by HCQ might arise as a valuable adjuvant in pancreatic ductal adenocarcinoma chemotherapy, regardless of p53 status [142,143]. |
| T482 |
2406-2610 |
Sentence |
denotes |
Given the same doses and route of administration, these inconsistencies between the two reported studies could probably derive from the use of p53 homozygous and heterozygous models of mice, respectively. |
| T483 |
2611-2719 |
Sentence |
denotes |
Regarding KRAS oncoprotein, its downstream pathway is one of the major players of pancreatic carcinogenesis. |
| T484 |
2720-2844 |
Sentence |
denotes |
The inhibition of this pathway by cytotoxic drugs, as well as trametinib, is often associated with an increase in autophagy. |
| T485 |
2845-3121 |
Sentence |
denotes |
For this reason, Drucker and Rosen [144] performed an off-label trial with an association of 400–1200 mg of HCQ and a constant dose of trametinib, observing a partial response with a general reduction of tumor lesion size, circulating tumor markers and cancer-associated pain. |